Project Summary: Heavy alcohol consumption is associated with a decline in cognitive ability with age and may contribute to neurodegenerative disease such as Alzheimer's disease (AD). However, the causal mechanisms underlying this association are essentially unknown. One of the major readouts of AD is a buildup of neurotoxic amyloid beta-peptide (A?) in the brain. The integral membrane enzyme ?-secretase cleaves amyloid precursor protein (APP), which in some conditions is converted to A? after proteolysis. ?-secretase also cleaves Notch, a highly conserved cell-signaling receptor. Several recent studies suggest that enhanced Notch signaling is instrumental in AD-associated neurodegeneration. Data derived from the parent R01 for this supplement suggests that alcohol directly activates Notch signaling in memory circuits in the Drosophila brain. Using a Drosophila model of AD, we will determine whether alcohol causally exacerbates AD pathology through the highly-conserved Notch signaling pathway. We hypothesize that alcohol increases Notch activity, which leads to enhanced AD pathology. Thus, genetically decreasing Notch activity will nullify the effects of alcohol on AD pathology. Together, this data may provide new pharmacological targets for developing more effective treatments for AD.